In this program project, we propose a Personalized Medicine approach to the study of advanced lung disease. We hypothesize that sub-phenotypes of common diseases, including pulmonary arterial hypertension (PAH), have a profound influence on outcome and responsiveness to therapy. The overarching translatlonal goal of this program is to define common mechanistic and therapeutic pathways for PAH in the context of major lung and systemic diseases, such as COPD and HIV. Our proposed three major projects and two cores are designed to integrate and synergize fundamental translatlonal research addressing major current and high impact problems in the PAH and advanced lung disease field. Because translational medicine requires a bench-to-bedside-to-bench integrated approach, we developed a full translatlonal continuum from preclinical models in three species, including a novel primate PAH model, screening and clinical drug development programs, human hemodynamic phenomic assessments, genetics, and clinical epidemiological trials focused initially on two major disease targets, COPD and HIV, which represent two prototypic models of the pulmonary hypertension sub-phenotype. Our three proposed projects and cores all individually and collaboratively align across this translational spectrum, driving an effort to understand fundamental mechanisms of disease, identify small molecule therapeutic agents, develop screening biomarkers for vascular sub-phenotypes of lung disease, and to set the stage for phase II and III clinical trials. Successes in the first five years of this project are expected to develop into phase ll-lll clinical trials and extension to other advanced lung diseases, such as interstitial lung disease and obstructive sleep apnea, in years 6 to 10. Project 1: Pulmonary hypertension in COPD: Genetic and Environmental Determinants Project 2: ROS signaling and NOS uncoupling in pulmonary vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core